PROJECTSUMMARY/ABSTRACT Thisproposaldescribesaconcertedapproachtothedesign,synthesis,andstudyofanovelreactiveself- assembly approach, templated by proteins. In this approach, the templating proteins are incarcerated as guests into a matrix of host polymers. The resultant nanoassemblies are programmed to release these encapsulatedproteinsintheirpristineforminthepresenceofaspecificbiologically-relevantstimulusordue to a combination of such stimuli. A key goal of the proposed research is to develop this into a new supramolecularplatformthatisusefulforabroadrangeofsolubleproteins,acapabilitythatdoesnotcurrently exist.Theprimarypremiseoftheproposedresearchthenistodevelopafundamentalframeworkforcustom- designing such supramolecular assemblies that can predictably encapsulate a protein, protect it from denaturationinnon-nativeenvironments,andregainitsnativestructureandfunctioninresponsetoastimulus that is specific to the target environment. We will identify the structural factors that underlie the formation of theseprogrammablemolecularassemblies.Wewilldevelopthisapproachandevaluateitsversatilitythrough: (i)elucidationofthefactorsthatcontroltheself-assemblyprocesssuchthattheapproachbecomesbroadly applicable to a wide-range of proteins;? (ii) incorporate responsive features in the assemblies for a range of specific intrinsic biological triggers, as well as specific combinations of such triggers;? and (iii) evaluation of strategiestotrafficproteinsacrossacellularmembranetoreleasetheminspecificintracellularcompartments. The proposed research will result inanovel, polymeric supramolecular platform with implications in several unmetchallengesinbiomedicine.